ABSTRACT With approximately 350 million people across the world suffering from Major Depression Disorder (MDD), effective treatment strategies targeted to unmet medical needs of these individuals need to be identified. Although behavioral therapies have offered encouraging outcomes, without the adverse effects of long-term use of pharmaceuticals, the lack of appropriate animal models has served as a barrier to understanding relevant biobehavioral mechanisms accompanying behavioral therapeutic approaches. The current R15 proposal focuses on a rodent model of a broad-based behavioral approach, Effort-Based Rewards (EBR), that was developed in the PI's laboratory. Building on findings of a recent R15 confirming neurobiological markers of resilience in EBR contingency-trained animals and flexible coping rats, the current proposal focuses solely on EBR behavioral training. The time course of relevant neurobehavioral transitions during EBR training (i.e., 5-6 weeks) will be established. Specifically, three aims are designed to deconstruct the multifaced nature of the depressive phenotype by (1) identifying behavioral shifts toward emotional resilience by mapping neuroplasticity modifications to two time-points of EBR training, (2) observing recalibrations in stress responsivity influenced by hippocampal mineralocorticoid and glucocorticoid receptors, as well as peripheral dehydroepiandrosterone (DHEA) and corticosterone levels, and (3) using chemogenetic techniques to manipulate a targeted brain area, the lateral habenula, and associated compensatory neural responses. Following training, animals will be assessed in various behavioral tasks designed to generate anxiety in uncertain conditions (i.e., prediction errors). It is hypothesized that, following EBR training, neuroplasticity measures will be enhanced through the time course of training; further, shifts from heightened stress responsiveness to emotional resilience will be driven by stress-related neuroendocrine modifications. Finally, chemogenetic activation of the lateral habenula is hypothesized to enhance understanding of the constellation of brain areas accompanying anxiogenic arousal. Thus, the proposed research will utilize an innovative preclinical model for behavioral therapeutic approaches and will facilitate the deconstruction of the MDD phenotype specifically related to the acquisition of behavior, recalibration of stress responsivity, and compensatory responsivity in relevant neural mechanisms. Undergraduate students and two collaborators will work with the PI to compete the proposed work.